WO2011079087, WO2015007516, WO2015007519, and WO2015007517 disclose amides of 3,5-diamino-6-halo-pyrazine-2-carboxylic acid of related structure showing ENaC (Epithelial Sodium Channel) inhibitor activity.
Venanzi teaches that the amino group in position 5 of the pyrazine moiety of amiloride and its analogs is essential for the stability of the blocking complex with ENaC (Venanzi et al., Journal of Medicinal Chemistry, 1992, Vol. 35 (9), 1643-1649).
The problem of the present invention is to provide further compounds for therapeutic use for the treatment of pathophysiological processes treatable by the blockade of an epithelial sodium channel, particularly for the treatment of the lungs and airways.
Such compounds should be potent inhibitors of ENaC. Suitable IC50 values determined in the Ussing Chamber assay are typically below 30 nM.
Additionally, such compounds should exhibit a low permeability which is beneficial for topical lung treatment. Suitable permeability values determined in the CALU-3 cells assay are typically below 6×10−7 cm/s.
Additionally, such compounds should have high solubility in aqueous media which is beneficial for administration by inhalation of an aqueous solution. Suitable solubility values in aqueous buffer with a physiologically acceptable pH value are 2% or higher.
Additionally, such compounds should have high hydrolytic stability in aqueous media which is beneficial for administration by inhalation of an aqueous solution.
Additionally, such compounds should inhibit in vivo water resorption in the lung upon topical administration. Topical lung administration of pharmacologically active doses of the compounds of the present invention should not or only to a low extent increase plasma aldosterone levels.
Surprisingly, it has been found that the claimed 3-amino-6-chloro-pyrazine-2-carboxylic acid derivatives which do not possess an amino group in position 5 of the pyrazine moiety are potent ENaC inhibitors and further possess the additional characteristics outlined above.